Integrins are a widely expressed family of calcium- or magnesium-dependent αβ heterodimeric cell surface receptors which bind to extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin, and osteopontin. These transmembrane glycoproteins (GP's), known for their large extracellular domains, are classified by at least 8 known β subunits and 14 α subunits (S. A. Mousa, et al., Emerging Theraupeutic Targets, 2000, 4, (2), 143-153). For example, the β1 subfamily, also known as the very late antigen (VLA) subfamily, has the largest number of integrins (S. A. Mousa, et al., Emerging Theraupeutic Targets, 2000, 4, (2), 144). The αvβ1 subfamily further associates with various β subunits: β3, β5, β6, β8 and αIIbβ3 (also referred to as GPIIb/IIIa) (S. A. Mousa, et al., Emerging Theraupeutic Targets, 2000, 4, (2), 144, 147). Some of the disease states that have a strong β3, β5 and GPIIb/IIIa integrin component in their etiologies are unstable angina, thromboembolic disorders or atherosclerosis (GPIIb/IIIa); thrombosis or restenosis (GPIIb/IIIa or αvβ3); restenosis (dual αvβ3/GPIIb/IIIa); rheumatoid arthritis, vascular disorders or osteoporosis (αvβ3); tumor angiogenesis, multiple sclerosis, neurological disorders, asthma, vascular injury or diabetic retinopathy (αvβ3 or αvβ5); and, angiogenesis (dual αvβ3/αvβ5) (S. A. Mousa, et al., Emerging Theraupeutic Targets, 2000, 4, (2), 148-149; W. H. Miller, et al., Drug Discovery Today 2000, 5 (9), 397-407; and, S. A. Mousa, et al., Exp. Opin. Ther. Patents, 1999, 9 (9), 1237-1248). The β3 subunit has received significant attention in recent drug discovery efforts. (W. J. Hoekstra, Current Medicinal Chemistry 1998, 5, 195) and antibodies and/or low-molecular weight compound antagonists of αvβ3 have shown efficacy in animal models (J. Samanen, Current Pharmaceutical Design 1997, 3, 545).
Furthermore, GPIIb/IIIa and αvβ3 antagonists have typically been designed after the bioactive arginine-glycine-aspartate (RGD) conformations of peptides derived from their primary ligands, fibrinogen and vitronectin, respectively. The RGD motif is the general cell attachment sequence of many extracellular matrix, blood, and cell surface proteins, as half of the ca. 20 known integrins bind the RGD-containing adhesion ligands. To discover RGD peptides with integrin selectivity, peptides with both restricted conformations and alterations of flanking residues have been studied. In particular, the structural requirements for interaction of the RGD sequence with GPIIb/IIIa and the inhibitory potential of a series of nonpeptidic mimetics on platelet aggregation and interactions with the extracellular matrix have been described (D. Varon, et al., Thromb. Haemostasis, 1993, 70(6), 1030-1036). Iterative synthesis of cyclic and alicyclic peptides and computer modelling have provided potent, selective agents as a platform for nonpeptide αv integrin antagonist design.
For example, PCT Application WO98/25892 to Fisher, et al., describes a series of α-sulfonamido and α-sulfinamido carboxylic acid compounds of the formula:
wherein    Y is selected from the group consisting of —COOH, —PO3H2, —SO3H and —COOR4; where R4 is selected from the group consisting of C1-10alkyl,    C1-8alkylaryl, arylC1-8alkyl, C1-8alkyloxycarbonyloxyC1-8alkyl,    aryloxycarbonyloxyC1-8alkyl, C1-8alkyloxycarbonyloxyaryl,    C1-10alkylcarbonyloxyC1-8alkyl and C1-8alkylcarbonyloxyaryl; A is selected from the group consisting of C6-12alkyl, C0-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-CO—NR5—C0-8alkyl, C0-8alkyl-O—C0-8alkyl,    C0-8alkyl-NR5—CO—C1-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-NR5—CO—C1-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-CO—NR5—C1-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-CO—NR5—C0-8alkyl-CO—N R5—C0-8alkyl,    C0-8alkyl-CO—C1-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-CO—C0-8alkyl-NR5—CO—CO0-8alkyl, C0-8alkyl-O—C2-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-O—C0-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-O—C2-8alkyl-O—C0-8alkyl-CO—NR5—C0-8alkyl, C0-8alkyl-S—C0-8alkyl,    C0-8alkyl-S(On)—C0-8alkyl, C0-8alkyl-S—C2-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-S(On)—C2-8alkyl-NR5—CO—C0-8alkyl,    C0-8alkyl-S—C0-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-S(On)—C1-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-NR5—CO—C0-8alkyl-S—C0-8alkyl,    C0-8alkyl-NR5—CO—C1-8alkyl-S(On)—C0-8alkyl,    C0-8alkyl-CO—NR5—C2-8alkyl-S—C0-8alkyl,    C0-8alkyl-CO—NR5—C2-8alkyl-S(On)—C0-8alkyl,    C0-8alkyl-NR5—C0-8alkyl-CO2—C0-8alkyl, C0-8alkyl-NR5—C0-8alkyl-CS—O—C0-8alkyl,    C0-8alkyl-NR5—C0-8alkyl-CO—NR5—C0-8alkyl,    C0-8alkyl-NR5—C0-8alkyl-CS—NR5—C0-8alkyl, C0-8alkyl-O—C0-8alkyl-CO2-C0-8alkyl,    C0-8alkyl-O—C0-8alkyl-CS—O—C0-8alkyl, C0-8alkyl-SiR7R8—C0-8alkyl,    C0-8alkyl-SiR7R8—C0-8alkyl-NR6—CO—C0-8alkyl and    C0-8alkyl-SiR7R8—C0-8alkyl-CO—NR6—C0-8alkyl; where R5, R6, R7 and R8— are independently selected from the group consisting of H and C1-6alkyl; and where    n=1 or 2; Z is selected from the group consisting of —NH—C(NR9R10)=R11, —NH—C(R9)=R11, —C(NR9R10)=R11 and piperidinyl; where R9, R10 and R11 are independently selected from the group consisting of H, C1-6alkyl, arylC1-3alkyl and aryl; or where two of the R9, R10 or R11 substituents form a cyclic ring containing (CH2)p, where p=2-5; R1 is H and R2 is selected from the group consisting of —SOm-aryl-, —SOm—C1-10alkyl-, —SOm-heteroaryl-, where m=1-2; R3 is selected from the group consisting of H, C1-8alkyl, aryl, C1-8alkylaryl and heteroaryl as inhibitors of RGD-dependent integrins for the treatment of thrombotic or restenotic disorders.
Accordingly, it is an object of the present invention to provide compounds that are antagonists of integrins. It is another object to provide isonipecotamide compounds that are αvβ3, αvβ5, GPIIb/IIIa, dual αvβ3/GPIIb/IIIa or dual αvβ3/αvβ5 integrin antagonists. It is a further object to provide methods for treating a variety of integrin-mediated disorders including, but not limited to, unstable angina, thromboembolic disorders, atherosclerosis, arterial and/or venous thrombosis, restenosis, rheumatoid arthritis, vaso-occlusive disorders, osteoporosis, tumor angiogenesis, multiple sclerosis, neurological disorders, asthma, vascular injury, macular degeneration or diabetic complications including diabetic retinopathy.